GENOX 1. Product Name - Medsafe

1 Page 1 of 7 NEW ZEALAND DATA SHEETGENOX1. Product NameGENOX, 10 mg and 20 mg, Qualitative and Quantitative CompositionEach tabletcontains 10 mg or 20 mgof tamoxifen (as citrate). For the full list of excipients, see section Pharmaceutical FormEach GENOX 10 tablet contains 10 mg of tamoxifen (as tamoxifen citrate). GENOX 10 is presented as white, biconvex, tablets, marked TN over 10 on one side and G on the GENOX 20 tablet contains 20 mg of tamoxifen (as tamoxifen citrate). GENOX 20 is presented as white, biconvex tablets, marked TN above a score and 20 below the score on one side and G on the Clinical Therapeutic indicationsGENOX is indicated for the treatment of breast and method of administrationAdultsThe initial dose is 20 mg once daily.

2 In advanced breast cancer, if no response is seen, dosage may be increased to 40 mg once is not indicated for use in must not be given during pregnancy. Premenopausal patients must be carefully examined before treatment for breast cancer to exclude the possibility of should not be given to patients who have experienced hypersensitivity to the Product orany of its excipients listed in section warnings and precautions for useAn increased incidence of endometrial changes including hyperplasia, polyps, cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying Page 2 of 7mechanism is related to the oestrogenic properties of tamoxifen.

3 Any patients receiving or having previously received tamoxifen, who report abnormal gynaecological symptoms, especially vaginal bleeding, should be promptly a large randomized trial in Sweden of adjuvant tamoxifen 40 mg/day for 2-5 years, an increased incidence of uterine cancer was noted. Twenty three of 1,372 patients randomized to receive tamoxifen versus 4 of 1,357 patients randomized to the observation group developed cancer of the uterus [RR= ; ( ), p< ].One of the patients with cancer of the uterus who was randomized to receive tamoxifen never took the drug. After approximately years of follow-up in the ongoing NSABP B-141trial, 15 of 1,419 women randomized to receive tamoxifen 20 mg/day for 5 years developed uterine cancer and 2 of the 1,424 women randomized to receive placebo, who subsequently had recurrent breast cancer and were treated with tamoxifen, also developed uterine cancer.

4 Most of the uterine cancers were diagnosed at an early stage, but deaths from uterine cancer have been reported. Patients receiving tamoxifen should have routine gynaecological care and report any abnormal vaginal bleeding to their an uncontrolled trial in 28 girls aged 2-10 with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration, mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. While this finding is in line with the pharmacodynamic properties of tamoxifen, a causal relationship has not been established. Tamoxifen is not approved for treatment of McCune Albright delayed microsurgerical breast reconstruction tamoxifen may increase the risk of microvascular flap number of second primary tumours, occurring at sites other than the endometrium and the opposite breast, have been reported in clinical trials, following the treatment of breast cancer patients with tamoxifen.

5 No causal link has been established and the clinical significance of these observations remains of visual disturbances, including infrequent reports of corneal changes, and common reports of retinopathy have been described in patients receiving tamoxifen therapy. Cataracts have commonly been reported in association with the administration of should be used cautiously in patients with existing leucopenia or thrombocytopenia. Leucopenia has been observed following the administration of tamoxifen sometimes in association with anaemia and/or thrombocytopenia. Neutropenia has been reported on rare occasions; this can sometimes be severe and rarely cases of agranulocytosis have been reported. Decreases in platelet counts, usually to 50,000 to 100,000/mm3, infrequently lower, have been occasionally reported in patients taking tamoxifen for breast cancer.

6 Periodic complete blood counts, including platelet counts, may be metabolisers of CYP2D6 may have a reduced response to tamoxifen due to reduced plasma concentrations of the active metabolite, endoxifen. Concomitant medicines that inhibit CYP2D6 may reduce the concentration of the active tamoxifen metabolite, endoxifen. Some studies have shown reduced efficacy of tamoxifen as measured by the risk of breast cancer recurrence and mortality, when taken with CYP2D6 inhibitors. Common CYP2D6 inhibitors include paroxetine, fluoxetine and bupropion. Women taking tamoxifen should avoid using CYP2D6 inhibitors wherever possible (see ).Use in premenopausal womenIt should be noted that only a small number of premenopausal women have been treated, since candidates for therapy are usually postmenopausal, either reaching a natural menopause, or having menopause induced by surgery or radiotherapy.

7 Menstruation is suppressed in a proportion 1 The NSABP (National Surgical Adjuvant Breast and Bowel Project) B-14 trial is undergoing reauditand information from this study may be subject to 3 of 7of premenopausal women receiving tamoxifen for the treatment of breast tumours. Cystic ovarian swellings have occasionally been observed in women receiving with other medicines and other forms of interactionWhen tamoxifen is used in combination with coumarin type anticoagulants, a significant increase in anticoagulant effect may occur. Where such co-administration is initiated, careful monitoring of the patient is tamoxifen is used in combination with cytotoxic agents, there is increased risk of thromboembolic events use of tamoxifen in combination with an aromatase inhibitor as adjuvant therapy has not shown improved efficacy compared with tamoxifen known principal pathway for tamoxifen metabolism in humans is demethylation, catalysed by CYP3A4 enzymes.

8 Pharmacokinetic interaction with the CYP3A4 inducing agent rifampicin, showing a reduction in tamoxifen plasma levels has been reported in the P450 2D6 (CYP2D6) plays an important role in the metabolism of tamoxifen. CYP2D6 helps convert tamoxifen to endoxifen (a potent active metabolite of tamoxifen). Therefore, co-administration of tamoxifen with CYP2D6 inhibitors such as paroxetine, fluoxetine and bupropion may reduce plasma levels of endoxifen and should be avoidedwhere possible (see section ) , pregnancy and lactationUse in pregnancy(Category B3)Tamoxifenmust not be administered during pregnancy. There have been a small number of reports of spontaneous abortions, birth defects and foetal deaths after women have taken tamoxifen, although no causal relationship has been toxicology studies in rats, rabbits and monkeys have shown no teratogenic rodent models of foetal reproductive tract development, tamoxifen was associated with changes similar to those caused by oestradiol, ethynyloestradiol, clomiphene and diethylstilboestrol (DES).

9 Although the clinical relevance of these changes is unknown, some of them, especiallyvaginal adenosis, are similar to those seen in young women who were exposed to DES in uteroand who have a 1 in 1000 risk of developing clear-cell carcinoma of the vagina or cervix. Only a small number of pregnant women have been exposed to tamoxifen. Such exposure has not been reported to cause subsequent vaginal adenosis or clear-cell carcinoma of the vagina or cervix in young women exposed in uteroto should be advised not to become pregnant whilst taking tamoxifenand should use barrier or other non-hormonal contraceptive methods if sexually patients must be carefully examined before treatment to exclude pregnancy.

10 Women should be informed of the potential risks to the foetus, should they become pregnant whilst taking tamoxifenor within two months of cessation of in lactationIt is not known if tamoxifenis excreted in human milk and therefore the drug is not recommended during on ability to drive and use machinesFatigue has been reported with the use of tamoxifen. Therefore, caution should be observed when driving or operating machinery while such symptoms effects The adverse reactions which have been reported are of two types: those associated specifically with the pharmacological action of the drug hot flushes, vaginal bleeding, vaginal discharge, pruritus vulvae, tumour pain and tumour flare and those of a more general nature, Page 4 of 7gastrointestinal intolerance, headache, light-headedness and, occasionally, fluid retention and alopecia.